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Differences in the transactivation domains of p53 family members: a computational study.

Mavinahalli JN, Madhumalar A, Beuerman RW, Lane DP, Verma C - BMC Genomics (2010)

Bottom Line: Folding simulation studies have been carried out to examine the propensity and stability of this region and are used to understand the differences between the family members with the ease of helix formation following the order p53 > p73 > p63.Differences in these interactions between the family members may partially account for the differential binding to, and regulation by, MDM2 (and MDMX).Phosphorylations of the peptides further modulate the stability of the helix and control associations with partner proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Institute (A-STAR), Matrix, Singapore. jagadeesh@bii.a-star.edu.sg

ABSTRACT
The N terminal transactivation domain of p53 is regulated by ligases and coactivator proteins. The functional conformation of this region appears to be an alpha helix which is necessary for its appropriate interactions with several proteins including MDM2 and p300. Folding simulation studies have been carried out to examine the propensity and stability of this region and are used to understand the differences between the family members with the ease of helix formation following the order p53 > p73 > p63. It is clear that hydrophobic clusters control the kinetics of helix formation, while electrostatic interactions control the thermodynamic stability of the helix. Differences in these interactions between the family members may partially account for the differential binding to, and regulation by, MDM2 (and MDMX). Phosphorylations of the peptides further modulate the stability of the helix and control associations with partner proteins.

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Evolution of secondary structures of the peptide variants at position 21, 22 and 24 along the simulation; Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil.
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Figure 6: Evolution of secondary structures of the peptide variants at position 21, 22 and 24 along the simulation; Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil.

Mentions: The above observations suggest that the electrostatic modification of p63 and p73 certainly has a significant effect on inducing and stabilizing helicity. To this, we now add the modification whereby we mutated I to L in p63 (taking cues from the differences we identified between p53 and p63 earlier) resulting in p63 with HIWD->DLWK (Movie S5). The long range interaction between D21 and K24 and a cluster of HBs between D21 side chain and back bone amines of W23, K24 and F25 initiate helix formation. Within 2-3ns, the C-terminus becomes fully helical and is stabilized by interactions of K24 with the anionic D21, E27 and the C-terminus (Figure 6). At the same time, at the N-terminus, a hydrophobic cluster comprising of residues F19, L22, F25 and L26 was observed to form and modulate the folding patterns. This hydrophobic cluster, which was quite stable when the L was an I at position 22, hindered the propagation of the helix; upon mutation, this cluster becomes relatively short lived, largely due to the larger fluctuations of L22 compared to those in I22. The ensuing destabilization of the hydrophobic cluster results in a transition of F19 away from F25 and this leads to propagation of the helix at N-terminus. Of course, in p73 we see a similar picture, but now the I22 leads to such propagation (peptide 6, Table 1, Movie S6), thus underlying the complexity of the relationship between sequence and folding patterns.


Differences in the transactivation domains of p53 family members: a computational study.

Mavinahalli JN, Madhumalar A, Beuerman RW, Lane DP, Verma C - BMC Genomics (2010)

Evolution of secondary structures of the peptide variants at position 21, 22 and 24 along the simulation; Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2822533&req=5

Figure 6: Evolution of secondary structures of the peptide variants at position 21, 22 and 24 along the simulation; Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil.
Mentions: The above observations suggest that the electrostatic modification of p63 and p73 certainly has a significant effect on inducing and stabilizing helicity. To this, we now add the modification whereby we mutated I to L in p63 (taking cues from the differences we identified between p53 and p63 earlier) resulting in p63 with HIWD->DLWK (Movie S5). The long range interaction between D21 and K24 and a cluster of HBs between D21 side chain and back bone amines of W23, K24 and F25 initiate helix formation. Within 2-3ns, the C-terminus becomes fully helical and is stabilized by interactions of K24 with the anionic D21, E27 and the C-terminus (Figure 6). At the same time, at the N-terminus, a hydrophobic cluster comprising of residues F19, L22, F25 and L26 was observed to form and modulate the folding patterns. This hydrophobic cluster, which was quite stable when the L was an I at position 22, hindered the propagation of the helix; upon mutation, this cluster becomes relatively short lived, largely due to the larger fluctuations of L22 compared to those in I22. The ensuing destabilization of the hydrophobic cluster results in a transition of F19 away from F25 and this leads to propagation of the helix at N-terminus. Of course, in p73 we see a similar picture, but now the I22 leads to such propagation (peptide 6, Table 1, Movie S6), thus underlying the complexity of the relationship between sequence and folding patterns.

Bottom Line: Folding simulation studies have been carried out to examine the propensity and stability of this region and are used to understand the differences between the family members with the ease of helix formation following the order p53 > p73 > p63.Differences in these interactions between the family members may partially account for the differential binding to, and regulation by, MDM2 (and MDMX).Phosphorylations of the peptides further modulate the stability of the helix and control associations with partner proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Institute (A-STAR), Matrix, Singapore. jagadeesh@bii.a-star.edu.sg

ABSTRACT
The N terminal transactivation domain of p53 is regulated by ligases and coactivator proteins. The functional conformation of this region appears to be an alpha helix which is necessary for its appropriate interactions with several proteins including MDM2 and p300. Folding simulation studies have been carried out to examine the propensity and stability of this region and are used to understand the differences between the family members with the ease of helix formation following the order p53 > p73 > p63. It is clear that hydrophobic clusters control the kinetics of helix formation, while electrostatic interactions control the thermodynamic stability of the helix. Differences in these interactions between the family members may partially account for the differential binding to, and regulation by, MDM2 (and MDMX). Phosphorylations of the peptides further modulate the stability of the helix and control associations with partner proteins.

Show MeSH